Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for the motor symptoms of medically refractory Parkinson's disease (PD). However, numerous questions remain on the therapeutic mechanisms of the technology. The fundamental goal of this Bioengineering Research Grant (PA-07-279) Competitive Renewal (NIH R01 NS047388) is to use detailed computer modeling techniques to augment neurophysiological investigation on the mechanisms of DBS. We hypothesize that therapeutic STN DBS induces basal ganglia (BG) network activity consistent with activation of axonal processes near the stimulating electrode, resulting in a regularization of BG input to the thalamus. In turn, thalamocortical processing can occur with reduced pathological interference from the BG during STN DBS. We propose to address this hypothesis with the integration of complementary data from three research modalities (experimental electrophysiology, computational modeling, and functional magnetic resonance imaging (fMRI)). First, we will parameterize a large scale neural network model to coincide with simultaneous multi-unit microelectrode recordings from the BG and thalamus of parkinsonian non-human primates. This experimental data will be acquired in collaboration with ongoing studies in the Vitek laboratory (NIH R01 NS037019;NIH R01 NS058945). Next, we will develop detailed patient-specific DBS models of the spread of stimulation in a cohort of 30 individuals using methodology developed in the PI's laboratory (NIH R01 NS059736). These patient-specific predictions of the neural tissue directly activated by their DBS will then be applied to the network model, allowing for evaluation of the network activity patterns generated by the stimulation. Finally, the integrated synaptic activity of the network model will be compared to fMRI data acquired in these same patients during DBS. This fMRI data will be acquired in collaboration with ongoing studies in the Phillips laboratory (NIH R01 NS052566). Our multi-disciplinary approach combines the strengths of each research modality and will provide a systems-level model of DBS. We will use our model to decipher the underlying neurophysiological changes responsible therapeutic benefit and define novel stimulation strategies that could improve clinical outcomes. PUBLIC HEALTH RELEVANCE: The basic goal of this project is to use computer modeling to better understand the clinical therapy of deep brain stimulation (DBS) for the treatment of Parkinson's disease. We propose that detailed models, based on experimental data, will provide a unified description of the mechanisms of the therapy. We will then use that knowledge to design more efficacious stimulation strategies for patients implanted with DBS systems.